sting at a crossroads: untapped potential for innate immunity
TRANSCRIPT
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STING at a Crossroads:Untapped Potential for
Innate ImmunityThomas W. Dubensky, PhD
Tempest TherapeuticsSouth San Francisco, CA
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Disclosures• Thomas W. Dubensky, Jr. is a paid employee of Tempest Therapeutics
and holds stock options in the company, and is an inventor on multiple patents and pending applications related to the STING pathway.
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STING at a Crossroads: Overview
• Scientific rationale for targeting STING, revisited
• Clinical-staged STING agonists, status and results
• Have expectations been met—is STING at a crossroads?
• Other approaches and rationale for targeting STING
• Concluding remarks
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Cytosolic DNA sensing pathwayRationale for Targeting STING
STING (Stimulator of Interferon Genes):
• Innate immunity is activated in response to sensing nucleic acids in the cytosol
• Downstream signaling is triggered through binding of cyclic dinucleotides (CDNs)
• CDNs are synthesized by bacteria or host enzyme cGAS in response to binding cytosolic DNA
• Bacterial and host-produced CDNs have unique structures which informs drug design
Ishikawa et al., Nature (2009); Burdette and Vance, Nature (2011); Motwani et al., Nat Rev Genetics (2018)
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Cytosolic DNA sensing pathwayRationale for Targeting STING
qRT-PCR
Listeria (Lm) intracellular infection Induced IFN-β expression
Luster, Moors and Portnoy, 1994 (unpublished); Woodward et al., Science, (2011); Burdette et al., Nature, (2011); and, Sauer et al., Infection and Immunity, (2011)
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Tumor-initiated T cell priming is STING-dependentRationale for Targeting STING
Tumor control
CD8α+ DC production of IFN-β in TME required for tumor inhibition
Fuertes et. al., JEM (2011); Woo, Gajewski, Immunity, (2014) CD8 T cell priming
Tumor-Initiated T cell priming and tumor control is STING—but not TLR-dependent
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Synthetic cyclic dinucleotides induce in situ priming and abscopal effectRationale for Targeting STING
Innate response
Corrales and Hix Glickman et al, Cell Reports (2015)
ADU-S100
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CDN induced anti-tumor efficacy is STING-dependentRationale for Targeting STING
Corrales and Hix Glickman et. al, Cell Reports (2015)
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Pre-clinical and clinical programsMultiple Groups are Targeting STING
Company Agent Delivery Program StageAduro/ Novartis ADU-S100 IT Small-molecule STING agonist Ph1/2Merck MK-1454 IT Small-molecule STING agonist Ph1/2Merck MK-2118 IT/ SubQ Small-molecule STING agonist Ph1Spring Bank SB11285 IT/ IV Small-molecule STING agonist Ph1GSK GSK3745417 IV Small-molecule STING agonist Ph1Bristol-Myers Squibb (IFM) BMS-986301 IT Small-molecule STING agonist Ph1Eisai E7766 Unknown Small-molecule STING agonist Precl/ DiscTakeda TAK-676 Unknown Small-molecule STING agonist Precl/ DiscTakeda/ Curadev CRD5500 Unknown Small-molecule STING agonist / “amendable to biconjugation as ADC” Precl/ DiscAbbvie (Mavupharma) MAVU-104 Oral ENPP1 inhibitor Precl/ DiscSynlogic SYNB1891 IT E. coli engineered to produce high levels of the STING agonist c-di-GMP Precl/ DiscSpring Bank SB11325/ 11396 IV Antibody conjugated STING agonists (Targets Unknown) Precl/ DiscTrillium Therapeutics TTI-10001 Unknown Small-molecule STING agonist Precl/ DiscCodiak Biosciences exoSTING Unknown Engineered exosome Precl/ DiscVenn Therapeutics VTX-001 IT Adenovirus that produces the bacterial STING agonist c-di-GMP Precl/ DisciTeos Therapeutics Unnamed IV Small-molecule STING pathway activators Precl/ DiscNimbus Therapeutics Unnamed Unknown Small-molecule STING agonist Precl/ DiscBicycle Therapeutics Unnamed Systemic Bicycle conjugateSelvita Unnamed Unknown Small-molecule to activate STING Precl/ DiscStimunity Unnamed Unknown Vectorized cGAMP – “virus like particle” Precl/ DiscStingInn Unnamed Unknown Small-molecule STING agonists/ nucleic acid-based STING activators Precl/ DiscStingInn/ Vyriad Unnamed Unknown Oncolytic viruses encoding STING pathway activators Precl/ DiscVenenum Biodesign Unnamed Unknown Small-molecule STING agonist Precl/ Disc
IT Intratumoral Systemic
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First Clinical Approach to Target STING: Intratumoral (IT)
Corrales and Gajewski., 2015, Clin. Can. Res.
Sponsor NCT# Agent Molecule Phase / Title
Aduro/ Novartis
NCT03172936
ADUS100/ MIW815 CDN
Study of the Safety and Efficacy of MIW815 With PDR001 to Patients With Advanced/Metastatic Solid Tumors or Lymphomas
Aduro/ Novartis NCT02675
439ADUS100/ MIW815 CDN
Safety and Efficacy of MIW815 (ADU-S100) +/-Ipilimumab in Patients With Advanced/Metastatic Solid Tumors or Lymphomas
Aduro/ Novartis NCT02675
439ADUS100/ MIW815 CDN Efficacy and Safety Trial of ADU-S100 and Anti-PD1
in Head and Neck Cancer
Merck NCT03010176 MK-1454 CDN
Study of MK-1454 Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001)
BMS (IFM) NCT03956680
BMS-986301 CDN
An Investigational Immunotherapy Study of BMS-986301 Alone or in Combination With Nivolumab, and Ipilimumab in Participants With Advanced Solid Cancers
Springbank NCT04096638 SB11285 SMNH*
Evaluating Safety and Efficacy of SB 11285 Alone and in Combination With Nivolumab in Patients With Advanced Solid Tumors
* Small Molecule Nucleic Acid Hybrid
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Clinical Results of Phase 1 Dose Escalation StudiesPublicly disclosed clinical results from ongoing Phase 1 studies with IT STING agonists
Aduro/Novartis (ADU-S100/MIW815): NCT03172936
Monotherapy Results Combination (Spartalizumab qmo) Results
41 pts with cutaneouslyaccessible lesions (10 melanoma, 2 uveal pts)
11/40 SD (28%)2/40 PR (5%)
53 pts (q3wk, 1 wk off)30 pts (q monthly)
12/53 SD (23%); 4/53 PR (8%); 1/53 CR (2%);3/8 ≥PR (38%) in PD1-naive TNBC pts; 2 PR in IO relapsed/refractory melanoma pts; 6/30 SD (20%) with q monthly CDN dosing
Merck (MK-1454): NCT03010176
Monotherapy Results Combination(Pembrolizumab) Results
20 pts with cutaneouslyaccessible lesions (5 melanoma pts)
4/20 SD (20%) 25 pts 6/25 SD (24%), 6/25 PR (24%); 3/8 PR (38%) in PD1-naïve HNSCC pts
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• Sporadic evidence of single agent activity across diverse tumor types
• No consistent observation of abscopal activity as a single agent
• No clear evidence of increased activity by combination with α-PD-1 mAb
• Some encouraging results:
• Aduro/Novartis: 3/8 ≥PR (38%) in PD1-naive TNBC pts and 2 PR in IO relapsed/refractory melanoma pts
• Merck: 3/8 PR (38%) in HNSCC in PD1-naïve pts
Are these first clinical results with IT STING agonists disappointing?
Clinical Results of Phase 1 Dose Escalation StudiesPublicly disclosed clinical results from ongoing Phase 1 studies with IT STING agonists
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• Sporadic evidence of single agent activity across diverse tumor types
• No consistent observation of abscopal activity as a single agent
• No clear evidence of increased activity by combination with α-PD-1 mAb
• Some encouraging results (single armed studies):
• Aduro/Novartis: 3/8 ≥PR (38%) in PD1-naive TNBC pts and 2 PR in IO relapsed/refractory melanoma pts
• Merck: 3/8 PR (38%) in HNSCC in PD1-naïve pts
Clinical Results of Phase 1 Dose Escalation StudiesPublicly disclosed clinical results from ongoing Phase 1 studies with IT STING agonists
Injected only 1 lesion mostly. Too early to say in combo. Appears safe and biomarker data is what we want. Looking forward to more!
@jasonlukemd
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STING at a Crossroads: Interpretation of Initial Clinical Results
• Differences between clinical studies
• Differences among molecules in clinical development
• Is STING being activated in the right cell types in the TME to initiate immunity?
• Is STING a validated target?
• Is intratumoral injection the right approach?
Deciphering the data
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STING at a Crossroads: Interpretation of Initial Clinical ResultsDifferences between clinical studies:
Aduro/Novartis: NCT03172936
Merck: NCT03010176
Deciphering the data
Cycle 1+
Week 1 2 3 4
X X X
X
Cycle 1 Cycle 2 Cycle 3 Cycle 4+Week 1 2 3 5 6 7 9 10 11 13 14 15
X X X X X X X X X X
Schedule A
Schedule B
Schedule
IT Injections
IT Injections
Dosing Schedule
Dosing Schedule
Doses Studied
Doses Studied
10 µg 1600 µg
10 µg 3000 µg
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STING at a Crossroads: Interpretation of Initial Clinical Results
• Differences among molecules in clinical development
• Aduro, Merck and BMS (IFM) molecules are CDNs Springbank molecule an SMNH
• Head-to-head studies have not been conducted
• CDN avidity and signaling can vary according to STING allele
• Molecules are not formulated—uptake among phagocytes, somatic cells and tumor cells can be variable
• The most potent STING ligand is not necessarily the optimal CDN for clinical development
Deciphering the data
* *
Tm S
hift
(o C)
* * ** * *
Rela
tive
IFN
-βex
pres
sion
* ADU-S100 (2Ꞌ 3Ꞌ S2-CDA)* cGAMP (natural ligand)
CDN-STING Thermal Stability(Differential Scanning Flourimetry)
STING activation in human PBMCs(IFN-β expression)
Corrales and Hix Glickman et. al, Cell Reports (2015)
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STING at a Crossroads: Interpretation of Initial Clinical Results
Is STING being activated in the right cell types in the TME to initiate immunity?• cGAS/STING is ubiquitously expressed
• STING pathway can be epigenetically silenced in tumor cells
• STING activation, and production of IFN-β leading to anti-tumor immunity can be initiated from diverse cells in the TME:
• Tumor cells, phagocytes, myeloid cells, stroma, endothelial cells
• Level of STING-induced IFN-β and TNF-α affects priming in the TDLN—a Goldilocks effect
Deciphering the dataGoldilocks effect of CDN-induced
CD8+ T cell priming
Baird et al. PLOS (2017); Baird et al. Cancer Res (2015); Corrales et al, Cell Reports (2015); Demaria et al. PNAS (2015); Francica et al., Can Immunol Res (2018); Sivick, et al, Cell Reports (2018)
SYSTEMIC DISTRIBUTION ->
DOSE ->
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STING at a Crossroads: Interpretation of Initial Clinical Results
Is STING a validated innate immune target?• Genetic validation—interferonopathies due to
dysregulation of STING pathway
Humans:
STING-associated vasculopathy with onset in infancy (SAVI) (ligand-independent activated STING)
Aicardi–Goutieres syndrome (AGS), chilblain lupus (TREX-1 mutation)
Epigenetic silencing of STING in tumor cells
DNA tumor virus inactivation of STING
Mice:
STING (TMEM173)-/-: HSV-1 virus infection sensitivity
TREX-1-/-: recapitulates human AGS
Deciphering the data
SAVI
Heart Skin Stomach
Trex
1-/-
Trex1-/- Mice
Gray et al., J. Immunol (2015); Ishikawa et al., Nature (2009); Lau et al. Science (2015); Liu et al., NEJM (2014); Stetson et al., Cell (2008); Xia et al., Cell Reports (2016)
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STING at a Crossroads: Interpretation of Initial Clinical Results
Is intratumoral injection the optimal approach?• Limited scope of indications: IT is a first step in
clinical development
• Consistency of injection
• Difficult to commercialize
• Unique antigenic repertoire between tumors may limit effectiveness of abscopal effect
• Broad activation of STING in TME globally leading to priming in multiple TDLNs
• Challenge with systemic delivery may be therapeutic index
Deciphering the data
Rejection Ag(s) in (injected) tumor X may be different from tumor X + 1
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Systemic Targeting of STING: Next Step in Therapeutic Development?
• Important next step in therapeutic advancement of innate immunity
• Activation of STING in TME globally leading to T cell priming in multiple TDLNs
• Challenge with systemic delivery may be therapeutic index given ubiquitous expression of cGAS/STING
Possible exception: Phase 1 First Time in Humans (FTIH), Open Label Study of GSK3745417 Administered to Subjects With Advanced Solid Tumors (NCT03843359)
IV administration (amidobenzimidazole)Ramanjulu et al., Nature (2018)
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The Race is On for Systemic Delivery
1st
Generation
2nd
Generation
Intratumoral Delivery
Intr
atum
oral
Syst
emic
Novel FormulationsNanoparticles, lipid-based,
etc.
“To improve the therapeutic window of STING agonist, iTeos selected Cristal Therapeutics nanoparticle technology to control the delivery towards the tumor microenvironment”Source: Company Website
“iTeos CEO Michel Detheux says… the target is instead another protein upstream of STING” Source: C&EN article*
“…non-nucleotide small molecules to indirectly and conditionally modulate the pathway, and we are leveraging this technology to develop orally bioavailable STING activators with first-in-class potential”Source: Financing PR – $20M Series A
Conjugated AntibodiesConjugating a STING agonist
to a tumor-directed antibody
[likely several groups]
STING PathwaycGAS, TREX1, ENPP1, IFI16 Small Molecule pro-
drugs
?[likely several groups]
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TREX-1 Inhibitor RationaleSystemic approach for targeting STING
• STING is ubiquitously expressed in immune and somatic cell populations
• TREX-1 maintains homeostasis by limiting activation of cGAS-STING in normal cells
• TREX-1 is induced by cytosolic DNA resulting from inflammation, DNA repair deficiency, and chemo/radiotherapy
• TREX-1 inhibition enhances dsDNA activation of cGAS and enzymatic production of cGAMP
• TREX-1 inhibitor is a systemic approach to localize / partition STING activation in the TME
Adopted from Li and Chen, JEM (2019)
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TREX-1 Inhibitor RationaleSystemic approach for targeting STING
Demaria. Nature Com, (2017), TREX1 regulates RT induced tumor immunogenicity
Radiation dose level has opposite effects on TREX-1 expression and IFN-β levels
High Dose RT induces Trex1 expression
Fractionated RT induces IFNβ
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Concluding Remarks
• STING is at a crossroads—early monotherapy clinical results did not reflect promise of preclinical studies
• Compelling genetic evidence in humans demonstrates that STING is a central mediator of cancer and autoimmunity
• Multiple players and approaches may reveal a better clinical approach for targeting the STING pathway—it’s the approach not the target
• Selective activation of innate immunity in the TME in metastatic disease with systemic therapies may be an optimal clinical approach for effectiveness